联合胃癌细胞系和肿瘤标本的基因表达分析，鉴定抗 HER 治疗的生物标志物——HAS2、SHB 和 HBEGF 的作用。
Combining gene expression analysis of gastric cancer cell lines and tumor specimens to identify biomarkers for anti-HER therapies-the role of HAS2, SHB and HBEGF.
机构信息
Technische Universität München, Fakultät für Medizin, Klinikum rechts der Isar, Institut für Allgemeine Pathologie und Pathologische Anatomie, 81675, München, Germany.
University Cancer Center Leipzig (UCCL), University Leipzig Medical Center, 04103, Leipzig, Germany.
出版信息
BMC Cancer. 2022 Mar 9;22(1):254. doi: 10.1186/s12885-022-09335-4.
BACKGROUND
The standard treatment for patients with advanced HER2-positive gastric cancer is a combination of the antibody trastuzumab and platin-fluoropyrimidine chemotherapy. As some patients do not respond to trastuzumab therapy or develop resistance during treatment, the search for alternative treatment options and biomarkers to predict therapy response is the focus of research. We compared the efficacy of trastuzumab and other HER-targeting drugs such as cetuximab and afatinib. We also hypothesized that treatment-dependent regulation of a gene indicates its importance in response and that it can therefore be used as a biomarker for patient stratification.
METHODS
A selection of gastric cancer cell lines (Hs746T, MKN1, MKN7 and NCI-N87) was treated with EGF, cetuximab, trastuzumab or afatinib for a period of 4 or 24 h. The effects of treatment on gene expression were measured by RNA sequencing and the resulting biomarker candidates were tested in an available cohort of gastric cancer patients from the VARIANZ trial or functionally analyzed in vitro.
RESULTS
After treatment of the cell lines with afatinib, the highest number of regulated genes was observed, followed by cetuximab and trastuzumab. Although trastuzumab showed only relatively small effects on gene expression, BMF, HAS2 and SHB could be identified as candidate biomarkers for response to trastuzumab. Subsequent studies confirmed HAS2 and SHB as potential predictive markers for response to trastuzumab therapy in clinical samples from the VARIANZ trial. AREG, EREG and HBEGF were identified as candidate biomarkers for treatment with afatinib and cetuximab. Functional analysis confirmed that HBEGF is a resistance factor for cetuximab.
CONCLUSION
By confirming HAS2, SHB and HBEGF as biomarkers for anti-HER therapies, we provide evidence that the regulation of gene expression after treatment can be used for biomarker discovery.
TRIAL REGISTRATION
Clinical specimens of the VARIANZ study (NCT02305043) were used to test biomarker candidates.
背景
对于晚期 HER2 阳性胃癌患者，标准治疗方法是曲妥珠单抗联合铂类氟嘧啶化疗。由于部分患者对曲妥珠单抗治疗无反应或在治疗过程中产生耐药性，因此寻找替代治疗方案和生物标志物来预测治疗反应成为研究的重点。我们比较了曲妥珠单抗和其他 HER 靶向药物（如西妥昔单抗和阿法替尼）的疗效。我们还假设，治疗依赖性的基因调控表明其在反应中的重要性，因此可以用作患者分层的生物标志物。
方法
选择一系列胃癌细胞系（Hs746T、MKN1、MKN7 和 NCI-N87），用 EGF、西妥昔单抗、曲妥珠单抗或阿法替尼处理 4 或 24 小时。通过 RNA 测序测量治疗对基因表达的影响，并在 VARIANZ 试验的可用胃癌患者队列中测试候选生物标志物，或在体外进行功能分析。
结果
在细胞系中用阿法替尼治疗后，观察到调节基因数量最多，其次是西妥昔单抗和曲妥珠单抗。虽然曲妥珠单抗对基因表达的影响相对较小，但可以鉴定出 BMF、HAS2 和 SHB 作为曲妥珠单抗反应的候选生物标志物。随后的研究证实，在 VARIANZ 试验的临床样本中，HAS2 和 SHB 是曲妥珠单抗治疗反应的潜在预测标志物。AREG、EREG 和 HBEGF 被鉴定为阿法替尼和西妥昔单抗治疗的候选生物标志物。功能分析证实 HBEGF 是西妥昔单抗的耐药因子。
结论
通过证实 HAS2、SHB 和 HBEGF 是抗 HER 治疗的生物标志物，我们提供了证据表明治疗后基因表达的调控可用于生物标志物的发现。
试验注册
VARIANZ 研究的临床标本（NCT02305043）用于测试生物标志物候选物。
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